Flaviviruses are a group of positive-stranded RNA viruses that have a global impact on public health due to their widespread distribution and ability to cause severe disease in humans. Several viruses in this genus, such as dengue (DENV) and West Nile (WNV) viruses, are considered emerging or re-emerging pathogens due to significant increases in morbidity and mortality observed during the past decade. Each year, an estimated 390 million individuals are infected by one of the four serotypes of DENV, resulting in roughly 250,000 cases of a severe and potentially fatal hemorrhagic manifestation of the disease. WNV is an encephalitic flavivirus introduced into North America in 1999 that has subsequently spread across the continent. WNV is now endemic in the United States. The potential for focal intense outbreaks of WNV, as occurred in 2012 in Texas, represents a significant threat to public health. Furthermore, while the clinical burden of WNV appears modest by comparison to other viral infectious diseases, long-term studies of morbidity in individuals that survive acute WNV infection suggest the true clinical burden of WNV disease in North America may not yet be realized. Humoral immunity is a critical aspect of host protection against flaviviruses; eliciting protective antibodies is a primary focus of ongoing vaccine development efforts for several of these viruses, including WNV and DENV. Complicating these efforts is the potential for antibodies elicited by natural infection or vaccination to modulate DENV pathogenesis and enhance disease. Antibody-dependent enhancement of infection (ADE) describes a dramatic increase in the infection of Fc-gamma-receptor-bearing cells in the presence of sub-neutralizing concentrations of antibody or immune sera. The biochemical and functional properties of a protective antibody response are not known. A primary goal of the VPS is to understand the mechanisms of humoral immunity against flaviviruses. We are investigating the molecular and structural basis of antibody-mediated neutralization and enhancement of flavivirus infection, while working to apply the knowledge and perspectives arising from these studies towards dissecting the functional properties of the polyclonal antibody response of naturally infected and vaccinated humans.